What We Did: During the current grant period we developed an innovative therapeutic approach to induce chronic states of tumor dormancy. It consists of integrating continuous low-dose chemotherapy (called "metronomic" dosing/scheduling) with molecular targeted antiangiogenic agents such as anti-VEGF receptor antibodies. This treatment concept, which has moved rapidly into clinical trial testing, may have the potential to change some of the prevailing paradigms of chemotherapy treatment, and to render various cancers currently considered untreatable using chemotherapy, susceptible to such drugs, but in a way that avoids the more acute and serious side effects generally associated with standard chemotherapy. What We Want To Do Next: This revised renewal application is designed to address a number of fundamental questions regarding mechanisms of antiangiogenic metronomic chemotherapy, answers to which could have a significant impact on improving its anti-tumor effects, the design of future clinical trials, as well as achieving a better understanding of the role of angiogenesis in tumor dormancy. These include: i) why does low dose metronomic chemotherapy appear to be selective for activated endothelial cells and not damage other types of normal dividing cells, and, in this regard, is an underlying mechanism induction of the endogenous inhibitor, thrombospondin-l? ii) how can optimum low-doses of particular drugs and drug combinations be determined? iii) does the treatment strategy have efficacy on advanced (high volume), drug resistant, metastatic disease?; iv) what mechanisms might compromise the efficacy of metronomic antiangiogenic therapies over time, and how can relapses be significantly delayed? Significance: The proposed basic research program has a high probability of significant translational impact, Le., to influence the implementation, and guide the design, of future clinical trials testing the metronomic antiangiogenic therapy concept. It also has the potential to uncover the basis of response versus resistance to antiangiogenic therapies, how tumor microenvironmental changes, e.g. hypoxia can alter response to antiangiogenic drugs, and point out new ways of integrating various molecular targeted therapies with conventional chemotherapeutic drugs so as to significantly enhance prolongation of survival without sacrificing quality of life.